Long-term follow-up

What are Long-Term Follow-Up studies?

As the field of gene therapy continues to evolve with new trends and emerging developments, it is imperative to stay up to date with the latest news and FDA regulatory guidelines. Of the key trends, real world evidence has been a fast-evolving requirement from regulatory bodies across the life sciences industry and even more so for gene therapies. The current approved therapies have already transformed patients’ lives, and with several more in the pipeline, gene therapy is expected to continue to transform the field as we know it. [4]

To fully understand the efficacy of a gene therapy product and long-term safety, it is important to monitor patients who are receiving therapy over an extended period of time. Regulatory agencies, including the FDA and EMA, have published guidelines highlighting the recommended study design and key data elements needed for the long-term follow-up (LTFU) studies generally. Although the current minimum duration of LTFU studies needed for AAV gene therapies is 5 years. [3]

For more information about the latest US regulatory guidelines please refer to the FDA guidance document Long Term Follow-up After Administration of Human Gene Therapy Products (fda.gov).

There are two types of LTFU studies associated with gene therapy clinical development. A brief overview of the two types along with the risks/benefits and challenges is shown in the following table. [3]

Note: As LTFU progresses from trial to real world settings, lighter touch approaches may apply.

What are the challenges of LTFU studies for AAV gene therapies?

There are several challenges to LTFU studies that are even more difficult for gene therapies. The list below highlights challenges we face in LTFU studies for AAV gene therapies; this list is not exhaustive. [1-4]

• Burden of data collection:  

  • Collecting and managing large volumes of data over an extended period – in the case for AAV gene therapies, a minimum of five years – can be time and resource consuming. Additionally, factors like patient engagement, data quality/analysis, and compliance can impact the data collection process.

• Limited patient population:  

  • The small and often sparse and scattered patient population for any given rare disease makes it challenging for studies to enroll an adequate number of participants. Additionally, patients may not follow up or may lose contact with their HCP due to life changes (e.g., relocating), which can affect your ability to monitor patients and continue collecting the LTFU data by the physician practice or treatment center.

It is important to note that patients with positive clinical outcomes may reduce their engagement with the healthcare system and are less likely to follow-up. This could result in LTFU that biases towards patients with poorer outcomes – something to keep in mind as you think about your LTFU needs.

• Disease progression and study design:  

  • Variability of other genes across the patient sample may have an unknown impact on the natural progression of the disease. To address this, it is important to explore relevant biomarkers in the LTFU study and identify associations, if any, between genetic variations in the study population and their clinical outcomes. This analysis can help you better understand the disease course and potential impact of your gene therapy on certain sub-populations. Additionally lack of knowledge, research, education on disease, biomarkers, etc. for rare diseases can make it hard to identify meaningful endpoints needed to measure safety and efficacy – the clinical end points may differ between patients, regulatory agencies, and payers.

• Study execution/operations:  

  • Monitoring patients over an extended period can pose challenges in terms of time, cost, and resources. The administrative burden associated with LTFU studies often leads to decreased interest from investigators. Consequently, lower incentive for participation and sustained engagement contributes to lost-to-follow-up of patients in the study.

• Safety considerations:  

  • Given how novel and innovative AAV gene therapies are, LTFU studies are a critical tool for monitoring long-term safety profiles due to uncertainties with dosing, potential for adverse events, and/or impact on patient’s quality of life.

What are the considerations and best practices to follow for LTFU studies?

While the current FDA minimum requirement for AAV gene therapy LTFU studies is 5 years, the following considerations and best practices are also highly recommended to ensure robustness in your LTFU study for your AAV gene therapy product. [1-4]

Considerations and best practices for LTFU studies

• Have a well-defined study design and implementation plan with an optimized efficient, timely, and high-quality data collection and monitoring system

  • Prioritize a systematic approach that incorporates clinical perspectives, regulatory requirements, data collection efficiencies, flexibility, and patient centricity

• Align your methods, goals, and approach with that of the regulators – considering the prolonged study period, keep a pulse on evolving FDA guidance

• Prepare to adapt based on emerging technology, evolution in disease understanding (e.g., biomarker partners, patient-mediated data, and services), and regulatory changes

• Draw insights around the therapy’s impact on the patient’s quality of life (e.g., frequency of follow-ups, interactions with clinicians)

  • Additionally, capture insights on how findings from LTFU studies can impact the ongoing clinical program

• Develop a patient support plan to engage with patients for the duration of the LTFU to minimize risk of loss-to-follow-up. Some ways you can do this include:

  • Providing telemedicine services and digital engagement solutions

  • Having a 24/7 patient support line

  • Supporting patient advocacy groups

  • Creating an information sharing portal

• Develop a registry or leverage an existing disease registry to track patients through follow-up to reduce some of the challenges/risks associated with LTFU studies

• Incorporate elements of decentralized clinical trial (DCT) solutions in the LTFU design to minimize the patient burden by reducing onsite follow-up, testing, and data collection

• Include a contingency or back-up plan around redosing or product failure/discontinuation

• Maintain a representative population as a key focus of the LTFU studies to ensure the patient population is adequately represented